The present invention relates generally to the transport of hyperpolarized gases from one site to another, such as from a production site to a clinical use site. The hyperpolarized gases are particularly suitable for MR imaging and spectroscopy applications.
Inert gas imaging (xe2x80x9cIGIxe2x80x9d) using hyperpolarized noble gases is a promising recent advance in Magnetic Resonance Imaging (MRI) and MR spectroscopy technologies. Conventionally, MRI has been used to produce images by exciting the nuclei of hydrogen molecules (present in water protons) in the human body. However, it has recently been discovered that polarized noble gases can produce improved images of certain areas and regions of the body which have heretofore produced less than satisfactory images in this modality. Polarized Helium-3 (xe2x80x9c3Hexe2x80x9d) and Xenon-129 (xe2x80x9c129Xexe2x80x9d) have been found to be particularly suited for this purpose. Unfortunately, as will be discussed further below, the polarized state of the gases is sensitive to handling and environmental conditions and can, undesirably, decay from the polarized state relatively quickly.
Various methods may be used to artificially enhance the polarization of certain noble gas nuclei (such as 129Xe or 3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization. Such an increase is desirable because it enhances and increases the MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U. S. Pat. No. 5,545,396 to Albert et al., the disclosure of which is hereby incorporated by reference as if recited in full herein.
A xe2x80x9cT1xe2x80x9d decay time constant associated with the longitudinal relaxation of the hyperpolarized gas is often used to characterize the length of time it takes a gas sample to depolarize in a given situation. The handling of the hyperpolarized gas is critical because of the sensitivity of the hyperpolarized state to environmental and handling factors and thus the potential for undesirable decay of the gas from its hyperpolarized state prior to the planned end use, e.g., delivery to a patient for imaging. Processing, transporting, and storing the hyperpolarized gasesxe2x80x94as well as delivering the gas to the patient or end userxe2x80x94can expose the hyperpolarized gases to various relaxation mechanisms such as magnetic field gradients, surface-induced relaxation, hyperpolarized gas atom interactions with other nuclei, paramagnetic impurities, and the like.
One way of minimizing the surface-induced decay of the hyperpolarized state is presented in U.S. Pat. No. 5,612,103 to Driehuys et al. entitled xe2x80x9cCoatings for Production of Hyperpolarized Noble Gases.xe2x80x9d Generally stated, this patent describes the use of a modified polymer as a surface coating on physical systems (such as a Pyrex(trademark) container) which contact the hyperpolarized gas to inhibit the decaying effect of the surface of the collection chamber or storage unit. Other methods for minimizing surface or contact-induced decay are described in co-pending and co-assigned U.S. patent application Ser. No. 09/163,721 to Zollinger et al., entitled xe2x80x9cHyperpolarized Noble Gas Extraction Methods, Masking Methods, and Associated Transport Containers,xe2x80x9d and co-pending and co-assigned U.S. patent application identified by Attorney Docket No. 5770-12IP, entitled xe2x80x9cResilient Containers for Hyperpolarized Gases and Associated Methods.xe2x80x9d The contents of these applications are hereby incorporated by reference as if recited in full herein.
However, other relaxation mechanisms arise during production, handling, storage, and transport of the hyperpolarized gas. These problems can be particularly troublesome when storing the gases (especially increased quantities) or transporting the hyperpolarized gas from a production site to a (remote) use site. In transit, the hyperpolarized gas can be exposed to many potentially depolarizing influences. In the past, a frozen amount of hyperpolarized 129Xe (about 300 cc-500 cc""s ) was collected in a cold finger and positioned in a metallic coated dewar along with a small yoke of permanent magnets arranged to provide a magnetic holding field therefor. The frozen gas was then taken to an experimental laboratory for delivery to an animal subject. Unfortunately, the permanent magnet yoke provided a relatively small magnetic field region (volume) with a relatively low magnetic homogeneity associated therewith. Further, the thawed sample yielded a relatively small amount of useful hyperpolarized 129Xe (used for small animal subjects) which would not generally be sufficient for most human sized patients.
There is, therefore, a need to provide improved ways to transport hyperpolarized gases so that the hyperpolarized gas is not unduly exposed to depolarizing effects during transport. Improved storage and transport methods and systems are desired so that the hyperpolarized product can retain sufficient polarization and larger amounts to allow effective imaging at delivery when stored or transported over longer transport distances in various (potentially depolarizing) environmental conditions, and for longer time periods from the initial polarization than has been viable previously.
It is therefore an object of the present invention to provide a transport system that can protect hyperpolarized gas products from potentially depolarizing environmental exposures during movement of the hyperpolarized gas products from a production site to a remote use site.
It is also an object of the present invention to configure a transport unit to serve alternatively or in addition as a portable storage unit, to hold polarized gases in their polarized state for longer periods including prior to shipment, or prior to delivery even if the gases are not intended to be remotely shipped.
It is also an object of the present invention to provide a portable unit for storing or transporting a quantity of hyperpolarized gas therein, which can substantially protect the hyperpolarized gas from the depolarizing effect of diffusion of the gas atoms through magnetic field gradients.
It is another object of the present invention to provide a portable unit for storing or transporting a quantity of hyperpolarized gas therein, which can substantially protect the hyperpolarized gas from the depolarizing effects of one or more of oscillating magnetic fields, electromagnetic noise, and electromagnetic interference (EMI).
It is another object of the present invention to provide a method of protecting the hyperpolarized gas from the depolarizing effects of undesirable EMI at a predetermined frequency or frequency range.
It is another object of the invention to provide a relatively compact, lightweight, easily transportable device which can provide sufficient protection for the hyperpolarized gas to allow the hyperpolarized gas to be successfully transported (such as in a vehicle) from a production site to a remote use site, such that the hyperpolarized gas retains a sufficient level of polarization at the use site to allow for clinically useful images.
It is another object of the invention to provide a valved hyperpolarized gas chamber configured to inhibit polarization decay (i.e., has relatively long decay times) during transport and/or storage.
It is another object of the invention to configure a transport unit to minimize the external force associated with shock, vibration, and or other mechanical collisions that are input into or transmitted to the hyperpolarized gas container.
It is another object of the invention to provide a protective enclosure for a transport unit which is configured such that the hyperpolarized gas held in an internally disposed hyperpolarized gas chamber may be directed out of or into the transport unit (i.e., the gas chamber may be filled and/or emptied), without the need to remove the gas chamber from its protective housing.
It is another object of the invention to configure a transport unit with an easily accessible means for interrogating the polarized gas held within the gas chamber held therein using nuclear magnetic resonance (NMR), in order to measure the polarization of the gas, or to measure the decay rate of the polarization.
It is another object of the invention to provide a means of adjusting the magnetic field strength generated by a transport unit, in order to shift the Larmor frequency of the spins associated with the hyperpolarized gas, either for purposes of NMR measurements, or to minimize decay from electromagnetic interference at a frequency of interest.
It is an additional object of the present invention to increase the shielding effectiveness of transport units.
It is still another object of the invention to provide a way to transport hyperpolarized gases from a polarization site to a secondary and/or tertiary distribution site while maintaining a sufficient level of hyperpolarization to allow clinically useful images at the ultimate use site.
These and other objects of the present invention are provided by the transport (and/or storage) units of the instant invention which are configured to protect hyperpolarized gas (and gas products and in one or multiple containers) held therein, thereby minimizing depolarizing losses introduced during transport of a hyperpolarized gas product from one place to another. In particular, a first aspect of the invention is directed toward a transport unit used to transport hyperpolarized products therein. The transport unit comprises at least one gas chamber configured to hold a quantity of hyperpolarized product therein and at least one electromagnet providing a magnetic holding field defining at least one region of homogeneity. The homogeneous region of the magnetic holding field is sized and configured to receive a major portion of the gas chamber (gas holding container) therein. The magnetic holding field is preferably primarily provided by a solenoid comprising at least one current carrying wire thereon. In one embodiment, the gas chamber is defined by a rigid body single or multi-dose container. In an alternative embodiment, the gas chamber is defined by a resilient body container with an expandable gas chamber (preferably sized and configured to hold a single patient dose).
In one preferred embodiment, a solenoid coil is configured to generate the magnetic holding field. Preferably the solenoid coil is also sized and configured to maximize the volume of the sufficiently homogeneous region provided thereby. Also preferably, the transport unit preferably includes one or more layers of an electrically conducting metal about the enclosure. As such, the enclosure can provide shielding from external electromagnetic radiation as well as mechanical support and protection. The transport unit may also include one or more layers of magnetically permeable materials, such as soft iron or mu-metal, to provide additional electromagnetic shielding, (including DC magnetic shielding), or to act as a flux return.
A further aspect of the present invention is a solenoid coil for providing a homogeneous magnetic field region in which the hyperpolarized gas is held. The solenoid comprises a cylindrical body and a first coil segment having a first coil length and a first number of windings disposed on the cylindrical body. The solenoid also includes second and third coil segments having respective second and third coil lengths and respective second and third number of windings disposed on the cylindrical body. The first, second, and third coil segments are spatially separated and positioned on the cylindrical body such that the second coil segment is intermediate the first and third coil segments. In a preferred embodiment, the second coil length is greater than both of the first and third coil lengths and the first and third windings are configured with a greater number of layers relative to the second winding. This coil configuration can advantageously provide a larger sufficiently homogeneous holding region for the hyperpolarized gas within a relatively compact coil area, thereby allowing the coil (as well as any associated transport unit) itself to be more compact while also providing for a useful dose of the hyperpolarized gas to be contained and protected therein.
Another aspect of the present invention is a hyperpolarized gas product container having a gas holding chamber and a capillary stem. The capillary stem has an inner diameter and length configured and sized such that the capillary stem preferably inhibits the migration or diffusional exchange of the hyperpolarized gas product between the main body of the chamber and the upper portion of the gas container which preferably includes a valve. More specifically, the capillary stem is sized such that the ratio of the main body volume to the volume in the capillary stem, multiplied by the diffusion time for 3He to traverse the length of the capillary, is greater than the T1 of a sealed chamber of the same material and dimensions. Exchange of gas product between the main body and the valve is udesirable because the valve is typically in a region of higher magnetic field gradients. Further, the valve may comprise materials that can undesirably introduce surface-induced relaxation into the polarized gas. The container itself may be configured as a rigid body or resilient body.
Yet another aspect of the present invention is a transport unit including at least one resilient container (and preferably a plurality of resilient containers) for holding a quantity of hyperpolarized gas (or liquid) product therein. In operation, one or more of the resilient containers are positionable within a homogeneous region of a magnetic field produced by the transport and/or storage unit.
Another aspect of the present invention is a system for distributing hyperpolarized gases, and preferably patient sized doses of hyperpolarized gases. The system includes a first transport unit which is sized and configured to hold a large multi-dose container therein. The system also includes at least one second transport unit sized and configured to carry a plurality of single dose containers therein. Preferably, the multi-dose container is a rigid body container and the single dose containers are resilient containers having expandable chambers to allow easy delivery or administration at a use site.
Similarly, in one embodiment, the multi-dose container is transported to a pharmaceutical distribution point where the hyperpolarized gas in the multi-dose container can be formulated into the proper dosage or mixture according to standard pharmaceutical industry operation. This may include solubilizing the gas, adjusting the concentration, preparing the mixture for injection or inhalation or other administration as specified by a physician, or combining two different gases or liquids or other substances with the transported hyperpolarized gas. Then, the formulated hyperpolarized product, substance, or mixture is preferably dispensed into at least one second container, and preferably into a plurality of preferably a single use size resilient containers which can be transported to a third or tertiary site for use. In a preferred embodiment, the first transport distance is such that the hyperpolarized gas is moved at increased times or distances over conventional uses. Preferably, the transport units and associated container of the present invention are configured such that during transport and/or storage, the hyperpolarized gas (particularly 3He) retains sufficient polarization after about 10 hours from polarization, and preferably after at least 14 hours, and still more preferably (especially for 3He) after about 30 hours. Stated differently, the transport units and associated containers of the instant invention allow clinical use after about 30 hours elapsed time from original polarization and after transport to a second site (and even then a third or tertiary site). The transporters and containers are also preferably configured to allow greater transit distances or greater transit times. Stated differently, the hyperpolarized product retains sufficient polarization after transport and greater elapsed time from polarization when positioned in the transport units to provide clinically useful images. This distribution system is in contrast to the conventional procedure, whereby the hyperpolarized gas is produced at a polarization site and rushed to a use site (which is typically relatively close to the polarization site).
An additional aspect of the present invention is directed toward a method of minimizing the relaxation rate of hyperpolarized noble gases due to external electromagnetic interference. The method includes the steps of capturing a quantity of hyperpolarized gas in a transportable container and shifting the resonant frequency of the hyperpolarized noble gas out of the frequency range of predetermined electromagnetic interference. Preferably, the method includes shifting the normal resonance frequency associated with the hyperpolarized gas to a frequency substantially outside the bandwidth of prevalent time-dependent fields produced by electrically powered equipment (such as computer monitors), vehicular engines, acoustic vibrations, and other sources. In a preferred embodiment, the resonant frequency of the hyperpolarized gas is shifted by applying a static magnetic field proximate to the hyperpolarized gas. For example, preferably for a hyperpolarized gas product comprising 3He, the applied static magnetic field is at least about 7 Gauss, while for hyperpolarized gas products comprising 129Xe, the applied magnetic field is at least about 20 Gauss.
Yet another aspect of the present invention is directed toward a system for preserving the polarization of the gas during transport. The system includes the steps of introducing a quantity of hyperpolarized gas product into a sealable container comprising a gas chamber at a production site and capturing a quantity of hyperpolarized gas product in the gas chamber. A magnetic holding field is generated by a portable transport unit defining a substantially homogeneous magnetic holding region therein. The gas chamber is positioned within the homogeneous holding region and the hyperpolarized gas product is shielded to minimize the depolarizing effects of external magnetic fields such that the hyperpolarized gas has a clinically useful polarization level at a site remote from the production site.
In a preferred embodiment, the step of providing the magnetic holding field is performed by electrically activating a longitudinally-extending solenoid positioned in the transport unit. The solenoid comprises a plurality of spatially separated coil segments, and the sealable container comprises a capillary stem in fluid communication with the gas chamber.
The present invention is advantageous because the transport unit can protect the hyperpolarized gas and minimize the depolarizing effects attributed to external magnetic fields, especially deleterious oscillating fields, which can easily dominate other relaxation mechanisms. The transport container is relatively compact and is, thus, easily portable. Preferably, the transport unit includes a homogeneous magnetic holding field positioned proximate to the gas container so that it provides adequate protection for the hyperpolarized state of the gas and facilitates the transport of the gas to an end use site. In a preferred embodiment, the transport unit includes a solenoid having at least a three-coil segment configuration with the central coil segment having a reduced number of wire layers compared to the other (opposing) two coil segments. Stated differently, the opposing end segments have a greater number of wire layers providing increased current density (current per unit length) in these areas. Advantageously, such a coil segment design can enlarge the homogeneous region of the magnetic field generated by the solenoid while minimizing the size (length) of the solenoid itself. This relatively compact transport unit can easily deliver a single patient dose or a plurality of patient doses (combined or individual).
Further, the transport unit is configured such that it can use an adjustable current to allow field adjustments, thereby enabling correction for one or more of electronic or mechanical drift, the type of gas transported, and severe exposure conditions. In addition, the transport unit can be employed with more than one type of hyperpolarized gas, for example, 3He or 129Xe. In addition, the transport unit can be configured such that the hyperpolarized gas can be released at the end use site without removing the typically somewhat fragile gas chamber from the transport unit (when glass chambers are employed). This capability can protect the gas from intermediate depolarizing handling and can also facilitate the safe release of the gas by shielding any users proximate to the transport unit from exposure to the internal gas container (such as a glass sphere) which is typically under relatively high pressure. Alternatively, the transport unit can shield resiliently configured gas containers to provide easy to dispense single dose sized products. In addition, the gas container preferably includes a capillary stem and/or a port isolation means which inhibits the diffusion or movement of the hyperpolarized gas out of the main body, thereby helping to retain a majority of the hyperpolarized gas within the homogeneous holding region and inhibiting contact between the hyperpolarized gas and the potentially depolarizing materials in the sealing means. Further, the enclosure walls of the instant invention are preferably configured such that they provide adequate spatial separation from the gas container to increase the shielding effectiveness of the transport unit.